Protective effect of fasudil, a Rho-kinase inhibitor, on chemokine expression, leukocyte recruitment, and hepatocellular apoptosis in septic liver injury

Journal of Leukocyte Biology

Yusheng Wang⁴  Jan E. Slotta¹  Karin Thorlacius²  Matthias W. Laschke¹  Bengt Jeppsson⁴  Michael D. Menger³  Henrik Thorlacius⁴ 

[1] Surgery, Malmö University Hospital, Lund University, Malmö, Sweden; and Institute for Clinical and Experimental Surgery, University of Saarland, Homburg/Saar, Germany Surgery, Malmö University Hospital, Lund University, Malmö, Sweden; and Surgery, Malmö University Hospital, Lund University, Malmö, Sweden; and Institute for Clinical and Experimental Surgery, University of Saarland, Homburg/Saar, Germany Institute for Clinical and Experimental Surgery, University of Saarland, Homburg/Saar, Germany Surgery, Malmö University Hospital, Lund University, Malmö, Sweden; and Institute for Clinical and Experimental Surgery, University of Saarland, Homburg/Saar, Germany;Anesthesiology and Intensive Care, Lund University Hospital, and Anesthesiology and Intensive Care, Lund University Hospital, and Anesthesiology and Intensive Care, Lund University Hospital, and;Institute for Clinical and Experimental Surgery, University of Saarland, Homburg/Saar, Germany Institute for Clinical and Experimental Surgery, University of Saarland, Homburg/Saar, Germany Institute for Clinical and Experimental Surgery, University of Saarland, Homburg/Saar, Germany;Surgery, Malmö University Hospital, Lund University, Malmö, Sweden; and Surgery, Malmö University Hospital, Lund University, Malmö, Sweden; and Surgery, Malmö University Hospital, Lund University, Malmö, Sweden; and

关键词: adhesion;    endotoxin;    intravital microscopy;    sepsis;   

DOI  :  10.1189/jlb.0705406

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

Rho-kinase signaling regulates important features of inflammatory reactions. Herein, we investigated the effect and mechanisms of action of the Rho-kinase inhibitor fasudil in endotoxemic liver injury. C57/BL/6 mice were challenged with lipopolysaccharide (LPS) and D-galactosamine, with or without pretreatment with the Rho-kinase inhibitor fasudil. Six hours after endotoxin challenge, leukocyte-endothelium interactions in the hepatic microvasculature were studied by use of intravital fluorescence microscopy and tumor necrosis factor α (TNF-α); CXC chemokines as well as liver enzymes and apoptosis were determined. Administration of fasudil reduced LPS-induced leukocyte adhesion in postsinusoidal venules and sequestration in sinusoids. Moreover, we found that fasudil abolished extravascular infiltration of leukocytes as well as production of TNF-α and CXC chemokines in the liver of endotoxemic mice. Liver enzymes and hepatocellular apoptosis were markedly reduced, and sinusoidal perfusion was improved significantly in endotoxemic mice pretreated with fasudil. Our novel data document that fasudil is a potent inhibitor of endotoxin-induced expression of TNF-α and CXC chemokines as well as leukocyte infiltration and hepatocellular apoptosis in the liver. Based on the present findings, it is suggested that inhibition of the Rho-kinase signaling pathway may be a useful target in the treatment of septic liver injury.

【 授权许可】

Unknown